Xenogenic tissue generally requires preservation prior to implantation in human beings. Without prior treatment, the tissue is rapidly enzymatically degraded and can elicit a severe immunological response. A large number of fixation techniques have been applied to xenogenic tissue in order to render it suitable for human implantation. The most common method involves the cross-linking of the tissue with glutaraldehyde (GA). Fresh tissue, without GA fixation, is destroyed after implantation by degradative enzymes. A common example of xenogenic tissue is Bio-Prosthetic Tissue (BPT), for example, porcine heart valve tissue, harvested from pigs, treated, and implanted into humans requiring new heart valves. The most common method used to treat BPT prior to implantation is treatment using glutaraldehyde fixation. The glutaraldehyde, having two aldehyde functionalities, can react with a tissue amino group at each end, thereby cross-linking the tissue, and rendering the tissue resistant to enzymatic degradation.
The use of GA fixed porcine heart valves was initially viewed as very promising to young heart valve recipients, as the BPT valves did not require the lifetime regimen of taking anti-coagulant and blood thinning drugs. However, GA fixed tissue proved subject to calcification, with implanted porcine heart valves often lasting only 10-15 years. Higher concentrations of GA may be used to decrease calcification, but this typically results in increased tissue stiffness. GA, while beneficial and commonly used for tissue fixation, also has a slight cytotoxic effect, and can also have an inflammatory effect.
Some researchers have attempted to modify bioprosthetic tissue with hydrogels. Applicants believe that many or all previous methods are limited by relying upon conventional GA cross-linking as an initial step. The GA cross-linking may link to most or all available amino groups in the tissue.
Attempts have been made to fill the GA fixed BPT tissue with a polymer, in order to reduce calcification. In particular, an attempt has been made to perform in-situ polymerization of acrylic acid monomers, to form the hydrogel poly acrylic acid in BPT tissue. See Nashef, U.S. Pat. Nos.: 4,729,139; 4,481,009; and 4,770,665.
Applicants believe that the dense GA cross-linked tissue does not allow for sufficient penetration of the hydrogel monomer molecules. Applicants believed that if tissue is initially fixed and thereby stiffened by GA cross-linking, then further filling with polymers might further stiffen the tissue, possibly making the tissue too stiff to serve some purposes, for example, as heart valve leaflets.
What would be desirable are methods for treating xenogenic tissue that resists calcification, resists initial biodegradation by matrix metalloproteases (MMPs), limits infiltration by inflammatory cells, elicits minimal immunogenic response, and does not increase tissue stiffness to a point rendering the implanted tissue unsuitable for its intended purpose.